This project delineates biochemical and pharmacological properties of sigma receptors and ligands. Using an affinity chromatography which purified sigma receptors by 2,000 folds in one step, a unique protein, with a pharmacological profile consistent with the original opioid/sigma receptor hypothesized by Martin etal., was discovered. This protein is sensitive to naloxone and the psychotomimetic benzomorphans such as cyclazocine and pentazocine. In a biochemical study, sigma receptors were found to reside in close proximity to IP3 receptors which mobilize extracellular and intracellular calcium. Behavioral, PRE-084 - a selective sigma ligand identified by this lab - was found to improve impairment of learning and memory in both the nimodipine-treated animals and in the genetically senescence-accelerated mice (SAM). Additionally, an agonist at the NMDA receptor-associated glycine site was found to reverse the 825-35 amyloid-induced amnesia. PRE-084 is currently being investigated to see if it may reverse the amnesia induced by 825-35 amyloid.